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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neurobehavioral and pathological data indicate that the central nervous system (CNS) becomes infected with HIV-1 soon after the virus enters the body. However, neuropathogenesis of HIV-1 infection is difficult to investigate because the brain parenchyma is not accessible to sampling during the course of AIDS. The second compartment of the CNS, cerebrospinal fluid (CSF), is accessible to sampling but how changes in the CSF relate to the changes in the parenchyma is poorly understood. Thus, knowledge of the neuropathogenesis of HIV-1 infection predominantly stems from either postmortem or in vitro studies. This raises the need for animal models of HIV infection of the CNS. Such models have been developed and are briefly reviewed here. The models faithfully recapitulate some aspects of the HIV/CNS disease. Appropriate neuropathological changes and neurobehavioral dysfunction (e.g., cognitive and motor deficits) occur in SIV-infected macaques. Central sensory electrophysiological changes and sleep disturbances occur in FIV-infected cats. Infection of the brain and behavioral changes comparable to some of the changes seen in humans occur in mice infected with a mixture of murine leukemia viruses. Genetically immunodeficient mice (e.g., SCID) accept HIV-infected human organs and or cell grafts. Evidence summarized here indicates that these HuSCID animals undergo neuropathological changes similar to those observed in brains of individuals who died with AIDS. Thus, presently available animal models provide an opportunity to investigate HIV/CNS disease, and to develop and test therapeutic interventions to prevent or cure the disease.
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PMID:Animal models recapitulate aspects of HIV/CNS disease. 757 36

An HIV-1 p17 subunit vaccine, HGP-30, was evaluated in 38 HIV-1 seronegative individuals in phase I clinical trials in U.K. and U.S.A. The vaccine preparation induced cytotoxic T-cell (CTL) (11/25) and lymphocyte proliferation responses to KLH (19/20) and HGP-30/p17 (24/29) as well as antibody responses to HGP-30 (29/38) and KLH (38/38). The CTL activity was observed in a higher number of vaccine recipients (9/18) in the lower dose groups (10 and 25 micrograms/kg) than the vaccine recipients (2/7) in the 50 and 100 micrograms/kg dose group. These observations suggest that the 10-25 micrograms/kg vaccine dose may preferentially induce TH1 cell responses. TH1 cell responses have been suggested as important in inducing protective cell mediated immunity. The CTL response has been shown to be CD8+. In a pilot study in SCID mice, HIV-1 virus challenge studies in mice reconstituted with cells from an HGP-30 immunized individual showed protection against virus challenge as compared to SCID mice reconstituted with cells from a non-immunized subject. These studies suggest that HGP-30 is capable of inducing protective cellular immunity.
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PMID:HIV-1 p17 synthetic peptide vaccine HGP-30: induction of immune response in human subjects and preliminary evidence of protection against HIV challenge in SCID mice. 758 Aug 34

The lack of a safe, economical murine lentivirus model for human immunodeficiency virus type 1 (HIV-1) infection of humans has hampered the preclinical evaluation of potential antiviral compounds, vaccines, and biological response modifiers. A small animal model that does not employ HIV-1 is needed to minimize risk of accidental human exposure, enhance efficient use of scarce experimental compounds, and reduce laboratory space necessary to conduct statistically significant in vivo trials. Feline immunodeficiency virus (FIV), an immunosuppressive lentivirus of domestic cats, has been used extensively as an animal model for the pathogenesis and therapy of human HIV-1 infection. Cats, however, are not amenable to large-scale efficacy trials because of their relatively large size, high cost, and limited degree of physiologic characterization, particularly with regard to drug metabolism. To adapt the feline immune system to a small laboratory animal host, severe combined immunodeficient mice (SCID mice) were engrafted with feline lymphoid tissues (forming the SCID-fe mouse) and inoculated with FIV. Two quantitative parameters, the incidence of provirus detection in feline tissue grafts and the level of feline IgG in plasma, were used to demonstrate the antiviral efficacy of 3'-azido-3'-deoxythymidine (AZT, azidothymidine, Retrovir, zidovudine) in the SCID-fe system. Of 17 SCID-fe mice inoculated with 7 x 10(6) peripheral blood mononuclear cells (PBMC) from an FIV-infected cat, eight had detectable FIV provirus in both the feline thymus and feline lymph node implants, as measured by polymerase chain reaction (PCR)/Southern blot analysis. Treatment of these mice with AZT at a dose of 125 mg kg-1 day-1 in drinking water beginning 1 day prior to FIV inoculation and continuing throughout the study interval prevented the dual detection of provirus in feline lymph node and thymus grafts of all mice tested. In a separate experiment, the level of spontaneous feline IgG production was quantified by ELISA 2 weeks after FIV inoculation with and without AZT treatment. Mean plasma feline IgG level of five SCID-fe mice inoculated with 10(3) TCID50 cell-free FIV was 2.23 mg ml-1. Mean feline IgG level of five mice inoculated with the same quantity of FIV and treated with AZT beginning 1 day prior to virus inoculation and continuing for 2 weeks thereafter was 14.98 mg ml-1. AZT significantly (P < 0.05) enhanced feline humoral immune function at a virus inoculum titer of 10(3) TCID50.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Reduced provirus burden and enhanced humoral immune function in AZT-treated SCID-feline mice inoculated with feline immunodeficiency virus. 761 56

SCID mice were engrafted with human foetal liver, thymus and lung. Human cells were subsequently detected among peripheral blood leukocytes for 81% of tested animals and in tissue implants for 100% of tested animals. SCID-hu mice received intraperitoneal injections of human immunodeficiency virus type 1 (HIV1) at from 20 up to 20,000 median tissue culture infectious doses (TCID5). HIV1 infection was detected by means of cell culture and polymerase chain reaction both in blood and implants, up to 58 days after infection. The rate of infection was dependent upon the inoculated dose: the frequency of thymus infection ranged from 14% with 20-500 TCID50 up to 100% with 20,000 TCID50. HIV1 infection was detected less frequently in blood leukocytes than in thymus. Thymus virus load ranged from 40 to 50,000 HIV1 provirus copies per million cells and was not correlated with either infectious dose or viraemia. Thymus T-cell depletion was observed mainly in the CD1+4+8+ immature thymocyte compartment. The same rate of SCID-hu mouse infection was obtained using three different primary HIV1 isolates, suggesting that infection was not restricted to a few particular virus strains. The systemic infection of SCID-hu mice following intraperitoneal virus injection mimics some traits of human HIV infection and provides a promising, novel approach for future investigations in this field.
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PMID:Dose-dependent systemic human immunodeficiency virus infection of SCID-hu mice after intraperitoneal virus injection. 763 34

We have investigated the in vivo pathogenic properties of two molecularly cloned strains of human immunodeficiency virus type 1 (HIV-1), HIV-1NL4-3 and HIV-1JR-CSF, in human fetal thymus/liver implants in severe combined immunodeficient mice. Studies comparing their in vivo replication kinetics and abilities to induce CD4+ thymocyte depletion were performed. HIV-1NL4-3 replicated in vivo with faster kinetics and induced greater levels of CD4+ thymocyte depletion than did HIV-1JR-CSF. These results demonstrate that different viral isolates have different pathogenic properties in this system. In the SCID-hu model, this pathogenesis most likely occurs in the absence of an immune response. Therefore, we investigated whether the absence of immune selection resulted in extensive genetic variation and the generation of viral quasispecies. To this end, DNA corresponding to the fourth variable domain region of the viral envelope gp120 protein recovered from biopsy samples at 6 weeks postinfection was sequenced. Little genetic variation was noted in either HIV-1JR-CSF- or HIV-1NL4-3-infected implants. The mutation levels demonstrated in both viral strains were more reflective of the acute rather than the chronic phase of HIV-1 infection in humans. These results suggest that the SCID-hu mouse model can be used to study the in vivo pathogenicity of different HIV-1 isolates in the absence of host immune selective pressures.
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PMID:In vivo pathogenic properties of two clonal human immunodeficiency virus type 1 isolates. 766 26

Monoclonal antibody BAT123 was passively transferred into SCID mice reconstituted with human peripheral blood lymphocytes (hu-PBL-SCID) to study passive antibody protection against human immunodeficiency virus type 1 (HIV-1) infection. BAT123 is specific for the third variable loop of the gp120 of HIV-1LAI. Animals were protected against subsequent infection with LAI strain, but not other virus strains, when BAT123 (1 mg/kg; 25 micrograms/mouse) was given 1 h before virus inoculation. This resulted in a peak serum concentration of 16 micrograms/mL of the antibody, which should be easily attainable in humans. In addition, postexposure protection was observed when the antibody was given within 4 h of virus inoculation. No therapeutic effect was observed, however, when BAT123 was administered after infection had been established. These results indicate that passive antibody prophylaxis against HIV-1 infection may be possible in certain clinical situations.
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PMID:Pre- and postexposure protection against human immunodeficiency virus type 1 infection mediated by a monoclonal antibody. 775 95

PBL from HIV-infected patients were engrafted into CB-17 SCID mice to develop a novel small animal model for the study of HIV pathogenesis and therapy. Engraftment was achieved in 84% of mice, with human Ig (hu-Ig) levels and total human mononuclear cell recovery by peritoneal wash similar to those in control hu-PBL-SCID mice engrafted with uninfected donor cells. The hu-Ig produced by hu-HIV/PBL-SCID mice had broad reactivity against HIV. Virus could be detected in 98% of mice by polymerase chain reaction and/or viral coculture. Viremia was first detected by quantitative polymerase chain reaction on day 7 (approximately 10,000 copies of viral RNA/ml of plasma) and persisted through day 17. Quasispecies analysis of amplified, cloned, proviral DNA of the V3 region of the env gene showed that nucleotide sequences from hu-HIV/PBL-SCID mouse peritoneal wash cells on day 17 were not significantly changed from those derived from donor PBL at the time of injection. Relative to human CD4+ T cell recovery by peritoneal wash in control hu-PBL-SCID mice (CD4 = 19 +/- 2%; n = 40), severe CD4+ lymphocyte depletion (CD4 = 5 +/- 0.5%; n = 59; p < 0.001) was observed in untreated hu-HIV/PBL-SCID mice 18 to 25 days after engraftment. Treatment with 2'-beta-fluoro-2',3'-dideoxyadenosine, a nucleoside analogue, significantly reduced CD4+ T cell depletion (CD4 = 13 +/- 1; n = 59; p < 0.001) and the frequency of virus isolation (70%; p = 0.015) in the hu-HIV/PBL-SCID model. Boosting hu-Ig levels in the mice by injection of purified donor Ig with neutralizing activity did not affect the frequency of CD4+ lymphocyte recovery or virus isolation. The administration of a mAb to TNF had minimal effects. These studies demonstrate that PBL from HIV-infected donors can engraft SCID mice; that HIV can be detected in the spleen, peritoneal wash cells, and blood of these mice; that HIV infection within the model results in rapid CD4+ T cell depletion; and that anti-retroviral therapy is effective in improving CD4+ T cell recovery and reducing the frequency of virus isolation. The hu-HIV/PBL-SCID mouse model thus represents a potentially useful model in which to study HIV pathogenesis and therapy.
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PMID:The human HIV/peripheral blood lymphocyte (PBL)-SCID mouse. A modified human PBL-SCID model for the study of HIV pathogenesis and therapy. 775 95

Human immunodeficiency virus (HIV) can form pseudotypes with other enveloped viruses, including herpes simplex virus, when the two viruses coinfect the same cell. Pseudotypes between HIV and Epstein-Barr virus (EBV) have not been described. We observed unusually high levels of HIV-1 replication in SCID mice transplanted with human peripheral blood mononuclear cells (hu-PBL-SCID mice) when the mice developed EBV-associated human B cell lymphoproliferative disease. If this enhancement of HIV-1 replication were due to pseudotype formation rather than direct infection of B lymphoblastic cells by HIV-1, the pseudotypes could pose a novel biohazard to laboratory workers. To assess whether HIV-1 and EBV can form such pseudotypes, we established and characterized CD4-positive B lymphoblastoid cell lines (LCL) that contained cells infected with both EBV and HIV-1. A high-titered virus pool from these LCL could induce HIV infection in the Burkitt's lymphoma (BL) line BJA-B, but not in the BL line Ramos. Infection of BJA-B was blocked by neutralizing antibody to HIV gp120 but not by neutralizing anti-EBV gp350. These experiments provide no evidence for pseudotype formation, suggesting a low risk for EBV:HIV pseudotypes in natural infection of humans or in human cells transplanted to SCID mice.
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PMID:Lack of pseudotype formation between human immunodeficiency virus type 1 and Epstein-Barr virus in productively coinfected B lymphoblastoid cell lines. 777 96

We have recently developed a modified SCID-hu mouse model in which the implanted human thymus and liver (hu-thy/liv) and human peripheral T cells become infected with HIV-1 after i.p. inoculation. By using this model, we evaluated the effect of HIV-1 infection on thymic maturation and observed that different HIV-1 strains had divergent effects of thymic maturation. Although minimal effects on continued thymopoiesis in the hu-thy/liv implant were observed after chronic infection with two primary patient isolates, HIV-1(28) and HIV-1(59), and with HIV-1ADA, HIV-1Ba-L, HIV-1JR-CSF, HIV-1JR-FL, and HIV-1SF162, significant thymocyte depletion was detected after infection with HIV-1IIIB and HIV-1RF. Thus, the effect of HIV-1 infection on thymocyte maturation may depend upon the strain of HIV-1 infecting the thymus. Despite the minimal effects on thymopoiesis observed in the hu-thy/liv implanted in SCID-hu mice 6 mo after infection with HIV-1(28), significant changes were seen in the human T cell population circulating in the peripheral blood of these mice. These changes ranged from an inversion of the CD4/CD8 ratio of peripheral human T cells in some SCID-hu mice to the almost complete depletion of peripheral human T cells observed in other SCID-hu mice. Because these effects were associated with the detection of HIV-1 infection of the peripheral human T cells, these modified SCID-hu mice should prove to be a valuable model for investigating the effects of chronic HIV-1 infection on the peripheral human T cell population.
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PMID:Divergent effects of chronic HIV-1 infection on human thymocyte maturation in SCID-hu mice. 781 92

Approximately one quarter of the AIDS patients have severe HIV encephalitis with diffuse neuronal damage that may be mediated by immune factors secreted by CNS macrophages. Based on an in vitro brain microsphere model, we developed an in vivo system in which human embryonic brain tissue survives for several months in the interscapular fat pad of SCID mice. Coculture of human brain tissue with macrophages prior to transplantation resulted in infiltration of the microspheres by activated macrophages. When the macrophages were infected in vitro with a neurotropic HIV strain, viral particles were detected in vivo up to 3 months after transplantation. HIV-infected transplants contained multinucleated giant cells similar to those seen in HIV encephalitis. However, the neuroglial component degenerated in the fat pad of SCID mice. The absence of synaptogenesis in the human transplants suggests that the murine fat pad lacks adequate stimuli or support for human neuronal differentiation. To study neurologic damage associated with HIV infection, sites of implantation that stimulate synaptogenesis (e.g. murine CNS) will need to be explored. Based on these findings we conclude that transplantation of brain microspheres with HIV-infected macrophages into SCID mice may be an achievable model of HIV encephalitis.
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PMID:In vivo model of HIV infection of the human brain. 783 48


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